The Svedberg Award 2004
Claes Gustafsson
Karolinska Institutet
Transcription in eukaryotic cells
Research Summary
We want to elucidate the molecular basis of regulated gene expression.
Of special interest to us is to understand how activators and
repressors can influence the rate by which individual genes are
transcribed. Most of our work concerns the nuclear RNA polymerase II
transcription machinery, but we also have an interest in the mechanisms
of mitochondrial transcription in human cells.
The Mediator complex acts as a bridge, conveying regulatory information
from enhancers and other control elements to the general transcription
machinery. The Mediator was originally identified in Saccharomyces
cerevisiae and is required for the basal and regulated expression of
nearly all RNA pol II dependent genes. Mediator complexes were later
also identified in metazoans, confirming a role for Mediator in
transcription regulation in higher eukaryotes as well. Mediator is
needed for the function of a large number, if not a majority, of human
specific transcription factors. Medically important transcription
factors, which operate via the Mediator include the nuclear hormone
receptors, the vitamin D receptor, Sp1, p53 etc. In spite of its
general significance for transcription control, the exact mechanisms of
Mediator function remain unclear. In our project, we aim to elucidate
the molecular basis of Mediator dependent tran-scriptional regulation.
A second line of research in the lab concerns the molecular basis for
regulated transcription in the human mitochondrion. The compact
mito-chondrial genome encodes for 13 key components in the respiratory
chain and the levels of mitochondrial transcription correlates with the
overall energy requirement of the eukaryotic cell. Surprisingly little
is known about the mechanistic and regulatory aspects of mitochondrial
transcription. We have recently identified two novel transcription
factors and for the first time reconstituted mammalian transcription in
vitro. Building on our unique in vitro system, we now work to elucidate
the biochemical basis for basal and regulated transcription in the
mammalian mitochondrion.